Immunoglobulins (Ig) are glycoprotein molecules that function as antibodies. Since antibodies are present in the bloodstream or bound to cell membranes, they are considered to be a part of the humoral immune system.
During an immune response, immunoglobulins bind to specific antigens (any foreign substance that is capable of inducing an immune response). Examples of antigens include bacteria, viruses, mold spores, dust mites, animal dander and fungus. Once the antibodies attach to the antigen, leukocytes (white blood cells) destroy the antigen.
There are five classes of immunoglobulins - IgA, IgD, IgE, IgG and IgM.
Antibodies are usually specific to each type of foreign substance. For example, antibodies produced in response to a tuberculosis infection attach only to tuberculosis bacteria. Antibodies are also involved in allergic reactions.
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isotypes (types of immunoglobulin)
IgA: Immunoglobulin A (IgA) antibodies are primarily found in the nose, airway passages, digestive tract, ears, eyes, saliva, tears and vagina. These antibodies protect body surfaces that are frequently exposed to foreign organisms and substances from outside of the body. The IgA antibodies make up about 10-15% of the antibodies found in the body.
IgG: Immunoglobulin G (IgG) antibodies are the smallest, but most abundant antibodies in the body, making up for 75-80% of all the antibodies in the body. They are present in all body fluids. In addition, they are the only antibodies that can cross the placenta during pregnancy. Therefore, the IgG antibodies of a pregnant woman help protect her fetus. IgG antibodies are considered to be the most important antibodies for fighting against bacterial and viral infections.
IgG isotypes are associated with complement fixation (binding of active serum complement to an antigen-antibody pair), opsonization (process by which antigens are altered so that they are more efficiently engulfed and destroyed by immune cells), fixation to macrophages and membrane transport.
There are four subclasses of the IgG class of antibodies -
IgG1, IgG2, IgG3 and IgG4. As the antibody-producing B-cell matures, it can switch from one subclass to another. In healthy individuals, 60-70% of IgG antibodies in the bloodstream are IgG1, 20-30% are IgG2, 5-8% are IgG3 and 1-3% are IgG4. The levels of IgG subclasses in the bloodstream vary with age. IgG1 and IgG3 reach normal levels by five to seven years of age, while IgG2 and IgG4 levels rise more slowly, reaching normal levels at about 10 years of age. In young children, the ability to make antibodies to bacteria (commonly antibodies of the IgG2 subclass) develops more slowly than the ability to make antibodies to proteins.
IgM: Immunoglobulin M (IgM) antibodies are the largest type of antibody. They are found in the bloodstream and lymph fluid. The IgM antibodies are the first antibodies that are produced in response to an infection. They also stimulate other immune system cells, including macrophages, to produce compounds that can destroy invading cells. IgM antibodies normally make up about 5-10% of all the antibodies in the body.
IgD: Immunoglobulin D (IgD) antibodies are found in small quantities in the tissues that line the abdominal and chest cavity of the body. The function of IgD antibodies is not well understood. Researchers believe they play a role in allergic reactions to some substances, such as milk, medications and poisons. IgD and IgE are present in very small amounts in normal human serum.
IgE: Immunoglobulin E (IgE) antibodies reside in the lungs, skin and mucous membranes. They induce allergic reactions against foreign substances like pollen, fungus spores, parasites and animal dander. IgE antibody levels are often high in people who have allergies. When IgE is active, the antibody triggers an allergic reaction called a hypersensitive reaction.
The allergen binds to the immunoglobulin on specific immune cells called basophils and mast cells. This binding results in the release of chemicals that cause inflammation in the body (like histamine, serotonin, proteases, bradykinin generating factor, chemotactic factors from various immune cells, leukotrienes, prostaglandins and thromboxanes) within 30 minutes of exposure. These chemical mediators cause allergy symptoms, such as urticaria (hives), runny nose, watery eyes, sneezing, wheezing and itching.
types of allergic reactions
Allergic reactions can be classified into four immunopathologic categories using various classification systems. These classifications are based on the immune system's response to the allergen, not on the severity of the reaction.
Type I: Type I allergic reactions involve immunoglobulin E (IgE), which is specific for a particular drug, antigen or other allergen that triggers the allergic reaction. The allergen binds to the immunoglobulin on specific immune cells known as basophils and mast cells. This binding results in the release of chemicals that cause inflammation in the body (like histamine, serotonin, proteases, bradykinin generating factor, chemotactic factors from various immune cells, leukotrienes, prostaglandins and thromboxanes) within 30 minutes of exposure. These chemical mediators cause allergy symptoms, such as urticaria (hives), runny nose, watery eyes, sneezing, wheezing and itching.
Type II: This classification is known as a cytotoxic reaction, involving destruction of the host cells. An antigen associated with a specific cell initiates cytolysis of the cell by an antigen-specific antibody, such as IgG or IgM. This reaction often involves blood elements such as red blood cells, white blood cells, and platelets. It often occurs within five to twelve hours after exposure to the allergen, which may include penicillin, quinidine, phenylbutazone, thiouracils, sulfonamides or methyldopa.
Type III: This category involves the formation of an antigen-antibody immune complex, which deposits on blood vessel walls and activates cell components known as complements. This causes a serum sickness-like syndrome, involving fever, swelling, skin rash and enlargement of the lymph nodes in about three to eight hours. It may be caused by a variety of allergens, including penicillins, sulfonamides, intravenous (IV) contrast media and hydantoins.
Type IV: This classification involves delayed cell-mediated reactions. Antigens on the allergen release inflammatory mediators in 24 to 48 hours. This type of reaction is seen with graft rejection, latex contact dermatitis and tuberculin reaction.
B cells are continually produced in the bone marrow.
Immature B cells only express IgM on their cell membrane. The immunoglobulin is on the cell surface. It is not secreted.
Once the B cell reaches maturity, it can express both IgM and IgD on the cell surface. This mature cell is now able to respond to antigens.
Once the immunoglobulin molecule interacts with an antigen, the B cell becomes activated and begins to divide and differentiate into an antibody-producing cell (plasma cell).
The activated B cell produces immunoglobulin that is secreted. Some of the daughter cells of the activated B cells undergo isotype switching. During this process, the B cell starts to express other isotypes of immunoglobulin.
If the B cell starts to mature abnormally, it will die in a process called apoptosis (programmed cell death).
Immunoglobulins are heavy plasma proteins. Each antibody is made of four polypeptides, two identical heavy chains and two identical light chains, which are connected by disulfide bonds to form a Y-shaped molecule.
The tips of the "Y" on the antibody form the fab (fragment antigen-binding) region. The amino acid sequence in the tips of the "Y" varies significantly among different antibodies. This region is made of 110-130 amino acids, and it gives the antibody its specificity for binding to an antigen. The amino acid region includes the ends of the light and heavy chains.
The fab region is divided into the hypervariable (HV) and framework (FR) regions. Hypervariable regions have a high ratio of different amino acids in a given position, relative to the most common amino acid in that position. There are three HV regions in the variable region -
HV1, HV2 and HV3. The HV regions bind directly with the antigen's surface. Therefore, HV regions are also called complementary determining regions, or CDRs.
The four FR regions, which have more constant amino acid sequences, separate the HV regions. The FR regions form a beta-sheet structure (two or more parallel adjacent polypeptide chains arranged so that hydrogen bonds can form between the chains). This provides support to the HV regions when they come into contact with an antigen.
The stem of the Y-shaped antibody is called the Fc (fragment, crystallizable) region. This region is responsible for the biological activity of the molecule, and therefore, determines the antibody's isotype.
Once the Fab section of the molecule binds to an antigen, the Fc region binds to the Fc receptors of immune system cells. For instance, IgM and IgG bind to phagocytic cells (like macrophages), while the Fc region of IgE binds to the receptors on basophils and mast cells.
Neutralization: Antibodies that recognize pathogens (disease-causing organisms) can block them by binding with them directly. Once an antibody binds to the pathogen, the pathogen is unable to infect a host cell. Antibodies, like IgA, can also bind to microbes in the mucus, which prevent the colonization of mucosal tissues. They can also neutralize toxins by binding with them.
Antibodies cannot bind to pathogens that have already entered a host cell. For instance, some viruses, such as HIV, HSV and HBV, are dormant inside the cell for long periods of time.
Agglutination: Antibodies are clonally produced to bind to specific antigens. The antibodies can link these antigens together, causing them to agglutinate (coagulate) so phagocytes (like macrophages) can engulf them.
Activation of complement: Immunoglobulin G and immunoglobulin M are able to activate the body's classical complement system. The complement system consists of more than 30 plasma and cell surface proteins that mark pathogens for phagocytosis (to be engulfed by macrophages) or kill them directly. When an antigen enters the body, antibodies bind to the surface of the antigen. Then the antibody attaches its Fc region to a complement protein, which initiates activation of the classical complement system.
Consequently, the antigen is killed in two ways. First, the binding process marks the antigen with a molecule that attracts the phagocytes, and then the phagocytes engulf the antigen. Second, some components of the complement system form a membrane attack complex to help the antibodies destroy the antigens directly.
Activation of effector cells: Phagocytic cells, lymphocytes, platelets, basophils and mast cells have specific receptors on their cells surfaces, which allow them to bind to antibodies. These are called Fc receptors. The Fc receptors are isotype-specific, which means they interact with the Fc region of specific antibodies. Once the Fc receptor is activated, it triggers the effector function of that cell. For instance, phagocytes will engulf the antigen, while mast cells will degranulate, triggering inflammation. The activation of effector cells leads to the destruction of the invading antigen.